Daily Sedation Interruption vs Continuous Sedation in Pediatric Patients Receiving Mechanical Ventilation

This systematic review and meta-analysis evaluates the clinical outcomes associated with daily sedation interruption vs continuous intravenous sedation in children receiving mechanical ventilation support.


Introduction
2][3] The goals of sedation are to be individualized and titrated according to the underlying pathology, with regular sedation assessments using validated tools (eg, Face, Legs, Activity, Cry, and Consolability scale; Ramsay Sedation Scale and Richmond Agitation Sedation Scale; COMFORT Scale or COMFORT Behavior Scale; and State Behavioral Scale for sedation) to ensure patients are optimally sedated when under MV support. 2 Targeting optimal levels of sedation to facilitate spontaneous breathing, prevent delirium, and minimize withdrawal risk and early mobilization is part of the holistic management of a mechanically ventilated, critically ill pediatric patient. 4,5tration to achieve the optimal depth of sedation to target the aforementioned goals while avoiding oversedation to minimize its adverse outcomes can be challenging due to interpatient variability affected by disease trajectory and evolution of disease. 6Associated short-term harm of continuous intravenous (IV) sedation in both undersedated or oversedated pediatric patients ranges from tolerance, withdrawal due to reduced kidney and hepatic metabolism, and morbidities such as prolonged MV and hospital stay. 7Neurotoxic properties of sedation in neuronal cells coupled with its interaction with critical illness brain stress and injury are potentially associated with long-term harm to the developing brains of children and adolescents. 8[11] However, insufficient evidence exists at present to allow for the direct extrapolation of adult data to pediatric practice. 12e such strategy to reduce excessive sedation exposure and its adverse outcomes is the use of daily sedation interruption (DSI), which refers to a temporary interruption of sedation, 13 in contrast to continuous administration.As most existing randomized clinical trials (RCTs) on sedation were based on adult populations, [13][14][15] little is known about the effectiveness of DSI in pediatric patients with regard to duration of MV, weaning off sedation, and incidence of adverse events (eg, agitation and accidental extubation).
This systematic review and meta-analysis updates an analysis of the use of DSI in pediatric patients, addressing the limitations of the previous systematic review and meta-analysis 12 done in 2018.Using current medical literature, the present analysis aimed to compare the clinical outcomes of DSI vs continuous IV sedation in patients receiving MV support in the pediatric ICU (PICU).

Search Strategy and Study Eligibility
With critical input from an experienced medical librarian (R.C.), we conducted a systematic search for studies using a combination of predefined keywords and Medical Subject Headings (pediatric intensive care unit, daily sedation interruption, continuous sedation infusion, and sedation protocol) in

JAMA Network Open | Critical Care Medicine
Interrupted vs Continuous Sedation in Mechanically Ventilated Patients 5 major databases: PubMed, Embase, Web of Science, CINAHL (Cumulated Index to Nursing and Allied Health Literature), and Cochrane Central Register of Controlled Trials from the time of database inception through October 31, 2023.We defined DSI as any temporary cessation in sedation and continuous IV sedation as the administration of sedative agents without interruption, which can include protocolized sedation with lighter sedation targets. 13There was no language restriction in the search strategy.This systematic review and meta-analysis was registered in PROSPERO (CRD42022314028).We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. 16e primary outcomes of interest were duration of MV and length of PICU stay.Secondary outcomes were mortality (all types of mortality rate measurements reported were accepted, such as PICU, hospital, and 28-day mortality), total sedative dose requirement (defined as total amount of sedative used during the PICU admission, standardized to a common unit [milligrams per kilogram] as appropriate to the sedative used), duration of sedation weaning (defined as duration in hours from the time a patient was deemed by the medical team to be fit for weaning off sedation to the time all sedation was stopped), and adverse events (eg, complications related to MV, withdrawal, and delirium).
Studies were included if the study cohort was aged 18 years or younger, required sedation for MV in the PICU, and reported at least 1 of the primary outcomes of duration of MV and/or length of PICU stay.We included systematic reviews, RCTs, and observational studies (both retrospective and prospective).Studies with a subpopulation who fulfilled the criteria were included if the data subset could be extracted.Studies from prospective databases, post hoc analyses of RCTs, or studies with a retrospective or prospective arm were also included as long as the study population fulfilled the criteria.Exclusion criteria were studies without a clear study design; studies conducted exclusively in the neonatal ICU, in the adult ICU, or with patients who received surgical anesthesia; conference abstracts or narrative reviews; and studies involving nonventilated patients requiring sedation in the PICU.

Data Extraction and Quality Assessment
Two of us (P.R.R. and K.H.Y.H.) screened titles and abstracts for eligibility and retrieved full-text articles for a thorough examination of their eligibility.Any disagreements were resolved by discussion and, if needed, adjudicated by an independent third party (T.S.W.T.).Data were collected from eligible studies by 2 of us (P.R.R. and K.H.Y.H.) using a standard data collection form.Data collected included author names and year of publication, clinical variables (including age, sex, presence of comorbidities or congenital defects, severity scores, PICU support modalities, and PICU admission diagnosis), description of DSI or continuous IV sedation drug used, sedation scores, sedation protocol, mean sedative doses used, duration of MV, length of PICU stay, duration of sedation weaning and mortality rate reporting, and any adverse events and neurological cognitive outcomes.
If required, missing data from the included studies were requested from the respective authors.
All results were tracked using the Covidence platform (Covidence).Assessment of the methodological quality of the studies was carried out using the Cochrane Handbook for Systematic Reviews of Interventions 17 for RCTs and the Newcastle-Ottawa Scale 18 for observational studies.

Statistical Analysis
A meta-analysis of all included articles was conducted using R, version 4.2.2 (R Project for Statistical Computing).We used a random-effects model to pool results from articles, accounting for variation between studies.The primary outcomes (ie, length of PICU stay and duration of MV) were treated as continuous data.Secondary outcomes of adverse events and sedative dosing were treated as binary and continuous data, respectively.Continuous outcomes were pooled using the mean difference (MD) or standardized MD, whichever was applicable; adverse events were pooled using risk ratios (RRs).All outcomes were reported with a 95% CI.Potential publication bias was presented in a funnel plot.If a study reported a median with IQR, the mean and SD were estimated by taking into account the sample size and smoothly changing weight in the estimation. 19Two-sided P < .05 was considered statistically significant.Heterogeneity was evaluated using the χ 2 -based q test and I 2 test. 20A q value less than 0.05 and I 2 greater than 50% indicated the possibility of significant heterogeneity. 21 address heterogeneity, subgroup analysis comparing medical vs surgical cohorts was performed.Additionally, the 7 domains of potential risk of bias were analyzed across all included RCTs.
After screening the titles and abstracts, we examined 41 full-text articles for eligibility.4][25] Five of the 6 studies 7,9,22,24,25 were conducted in a mixed PICU, while 1 study 23 was in a cardiac-surgical PICU.Two RCTs were conducted in Asia (India and Indonesia; n = 142), 2 in Europe (the Netherlands; n = 159), and 2 in North America (US; n = 2509) (Table ).There was blinding in 3 RCTs, 7,9,23 while 2 were nonblinded studies. 22,25All except 1 study 24 included both midazolam and morphine as firstline medications in the protocol, with variations in dosing regimens and allowances for alternatives, such as fentanyl, in the event of hemodynamic instability or reactive airway disease. 22In 3 of 6 RCTs, 7,22,23 the sedation protocol was nurse driven with physician oversight.

Study characteristics, including inclusion and exclusion criteria, are summarized in the Table.
Patient characteristics, sedation regimens and dosing, and outcomes are summarized in eTables 1 to 3 in Supplement 1.The most common medical indications requiring admission to the PICU for MV had respiratory etiologies (2323 [82.7%]), including acute respiratory distress syndrome, bronchiolitis, pneumonia, and status asthmaticus. 7,9,22Other medical indications included cardiomyopathy and congenital heart disease, septic shock, and neurological reasons. 7,9,24,25The most common surgical indications requiring admission to the PICU were postoperative cardiac surgical procedures, ranging from atrial septal defect or ventricular septal defects to repair of total anomalous pulmonary venous drainage or tetralogy of Fallot. 23dazolam was the most common sedative agent assessed across all RCTs, followed by morphine in 5 RCTs. 7,9,22,23,25Clonidine, ketamine, and fentanyl were examined in 2 RCTs. 7,22xmedetomidine and lorazepam were evaluated in 1 RCT 22 and propofol in another RCT. 7Dosing regimens for the sedatives and protocols used for DSI varied across the trials according to their respective institutional practices.Study methodologies are described in eTable 2 in Supplement 1.

Association of DSI With MV Duration and Length of PICU Stay
Five RCTs reported the primary outcomes of duration of MV 7,9,22,24,25 and length of PICU stay. 7,9,22,23,25Patients in the DSI group had a shorter duration of MV compared with patients in the continuous IV sedation group (5 studies, 7,9,22,24,25 n = 2750; MD, −0.93 [95% CI, −1.89 to 0.04] days), although the results were not significant (P = .06)(Figure 2).Meta-analysis of these 5 studies 7,9,22,23,25 revealed that the DSI group had a shorter length of PICU stay compared with the continuous IV sedation group (n = 2770; MD, −1.45 [95% CI, −2.75 to −0.15] days), and these results were significant (P = .03)(Figure 3).One RCT 24 was excluded due to incomplete data for the DSI group and no data reported for the control group.

Association of DSI With Sedative Dosing and Adverse Events
Secondary outcomes were similar in both DSI and continuous IV sedation groups (eFigures 1 and 2 in Supplement 1), with no significant difference detected in total doses of midazolam (3 studies, The most commonly reported adverse event in the continuous IV sedation group vs the DSI group was accidental extubation (0.6% vs 0.4%) in 5 RCTs. 7,9,22,24,25Other adverse events reported in the continuous IV sedation group vs the DSI group were pneumothorax (0.5% vs 0.4%), inadequate analgesia (12.4% vs 13.9%) vs oversedation (0.1% vs 0%), withdrawal (8.1% vs 10.6%),  hemodynamic instability (0.1% vs 0.1%), ventilation-associated complications, such as postextubation stridor (3.9% vs 6.3%), and immobility-related complications such as ulcers (1.4% vs 0.4%) (eTable 3 in Supplement 1).No adverse events were noted in 1 RCT, 23 and mortality data were not reported in 2 RCTs. 23,24Delirium was not described as an outcome of interest in all included studies.One RCT 22 reported that delirium could not be assessed because pediatric assessment tools were unavailable on commencement of the trial.

Subgroup Analysis
Duration of length of PICU stay was compared between medical and surgical cohorts to ascertain whether DSI had a comparable outcome between both cohorts.In the medical cohort (2 studies, 22,25  ).Two RCTs 7,9 were not included due to mixed data between medical and surgical cohorts, and data were not available for 1 RCT 24 with a purely medical cohort.Subgroup analysis for the duration of MV was not carried out due to incomplete data from the 1 RCT 23 with a purely surgical cohort.

Risk of Bias
Selection and reporting biases were low in most of the 6 RCTs, although performance and detection biases were higher because blinding was not standard across all study methodologies (Figure 4).
Attrition bias and other biases were also low across the studies.The number of patients lost to follow-up was assumed to be minimal or 0 given that the patients were followed up until time of   discharge from the PICU or the hospital.One RCT 9 followed up the cohort for 1 year after study enrollment.Two RCTs 24,25 did not provide data on patients lost to follow-up.The asymmetric funnel plot raised concerns for a potential publication bias likely attributed to study heterogeneity (eFigure 4 in Supplement 1).

Discussion
Since the 2018 systematic review and meta-analysis on DSI in pediatric patients, 12 there have been considerable advancements in the provision of sedation in critically ill patients.The present systematic review and meta-analysis found that DSI was associated with reduced length of PICU stay in patients who received DSI.There was no significant difference in MV duration, total doses of midazolam and morphine used, or adverse events between patients in the DSI and continuous IV sedation groups.
One of the proposed benefits of DSI is a lower risk of oversedation and, in turn, lower risk of remaining intubated and ventilated for a prolonged period, which has inherent complications such as ventilator-associated pneumonia. 3This benefit was observed in the previous systematic review and meta-analysis on pediatric DSI, 12 which was consistent with findings in a systematic review on adult DSI 3 but was not consistent across other adult studies. 26,27The discrepancy within the findings could be attributed to study heterogeneity, as ventilatory requirements may vary across different disease pathologies as well as different MV weaning strategies across different studies.In addition, disease pathologies requiring invasive therapies (eg, extracorporeal membrane oxygenation or continuous kidney replacement therapy) or surgical conditions (eg, postoperative neurosurgical interventions or cardiac surgical procedures requiring deeper sedation or delayed weaning to mitigate withdrawal risk) may inevitably prolong MV duration in pediatric patients. 28However, certain cohorts, such as postsurgical patients, once extubated and off sedation, may experience shorter overall length of PICU stay.Similar heterogeneity was seen across the RCTs as evidenced by differences in target populations, which will incontrovertibly confound the outcomes of DSI and interpretation of its perceived benefits.However, we used a random-effects model in an attempt to account for effect heterogeneity because the true effect size may not be same across all studies.
While there is a risk of insufficient sedation leading to agitation secondary to pain and, in turn, adverse outcomes such as accidental extubation, 29 DSI potentially enables patients to wean off their sedation faster without worrying about drug bioaccumulation, get extubated sooner, and thus leave the PICU earlier. 30In the RCTs analyzed, reduced duration of PICU stay in the DSI cohort was similarly observed by Verlaat et al 9 and Gupta et al. 25 This finding was also noted in a systematic review of 45 RCTs with 5493 adults admitted to the ICU whereby DSI was associated with shorter overall length of ICU stay. 3 However, this was not a consistent finding in other systematic reviews involving adult patients. 13,26One can posit that confounding factors, such as the course of an illness and associated complications, a poor premorbid state or other comorbidities, and greater severity of illness in terms of higher mortality scores, can also contribute to an extended ICU stay, which may not always be directly affected by sedation practices. 31though we found that the DSI group had a shorter length of PICU stay, it did not correspond to a significantly shortened duration of MV; however, there was still a reduction of 0.93 days compared with the continuous IV sedation group.One may expect that a shorter PICU stay would go in tandem with a shorter duration of MV.A finding from this study was similar to that noted in another systematic review 32 comparing outcomes of duration of MV, length of ICU stay, and hospital mortality between pediatric and adult patients in DSI vs continuous IV sedation groups: overall, the duration of MV, length of ICU stay, and total sedative dose were not reduced even in the DSI cohort because of the heterogeneity of the studies included.We postulated that this observation can be attributed to institution-dependent sedation weaning strategies to prevent complications (eg, withdrawal or delirium), illness trajectory or postsurgical course, elective admissions to the PICU, and difference in the proportion of patients with chronic illness.However, it is plausible that patients could have stayed in the PICU for other sedation sequelae, such as delirium, which were not reported in the RCTs.
The present examination of all RCTs on this topic to date showed that while there was no difference in duration of MV or sedative dosing, there was no difference in mortality outcome, and the overall length of PICU stay was reduced with no difference in adverse outcomes, suggesting that less sedation (DSI) may be as safe or safer than more sedation (continuous IV infusion).This is contrary to a 2022 Italian consensus guideline on analgosedation in patients admitted to the PICU, 30 which cautioned against the use of DSI in view of conflicting RCT findings that DSI was not associated with reduced duration of MV, length of ICU stay, and amount of sedation but was associated with increased mortality.Nonetheless, the authors of the Italian guidelines also reinforced that implementation of a DSI protocol should not be the only factor in improving overall quality of care but should be part of a framework that includes educating the health care team and empowering nurses regarding reducing unnecessary sedation for better outcomes of intubated and ventilated patients in the PICU. 33This finding was also echoed in a review of sedation protocols in the ICU by Balit et al, 34 which showed that while there was no difference in the duration of MV or length of PICU stay, a sedation protocol helped with keeping patients calmer when awake as well as improving overall interprofessional communication by establishing clearer goals of care to maintain sedation targets with regular sedation assessments.We believe that a DSI protocol alone may not change overall outcomes, but it would play a role in improvement of outcomes.We recommend that future studies compare important clinical outcomes before and after implementation of sedation protocols, with DSI as part of the care bundles in PICUs.
We did not find evidence of a difference in adverse events between the DSI and continuous IV sedation groups, contrary to the previous systematic review and meta-analysis, 12 which reported a slightly higher rate of adverse events in the DSI group.While 1 RCT 22 reported significant adverse events, the other 6 studies did not find many, which reflects the lower risk profile of DSI in pediatric patients.Accidental extubation, withdrawal and need for restraints, and inadequate pain control are all possible risks, but the managing medical and nursing teams should tailor the DSI regimen on a case-by-case basis.It would be appropriate to start this practice in patients with a lower risk profile rather than in patients with a higher risk profile, such as those with a difficult airway.Moreover, there are possible confounders contributing to an increased risk of adverse events, such as depth of sedation, nursing manpower, and, in turn, quality of nursing care rendered to each patient. 35is study also did not show a significant difference in sedative dosing.In contrast, the review by Balit et al 34 showed a favorable outcome from sedation protocols associated with reduced midazolam dose without corresponding harm to patients in terms of adverse events and ability to meet sedation targets.There is growing evidence 30,36,37 that midazolam has adverse implications for neurocognitive development and has a dose-dependent association with delirium.Further longitudinal studies are needed to identify long-term psychological outcomes, such as posttraumatic stress disorder, anxiety, and depression. 38While studies have shown no harm associated with transient anesthesia use in pediatric patients, a study on patients aged 0 to 8 years with acute respiratory failure requiring PICU admission and subjected to PICU interventions and sedation for many days reported that these patients had an overall lower intelligence quotient compared with well siblings within the same household. 39Hence, long-term neurodevelopmental outcomes remain important considerations for an intensivist managing critically unwell pediatric patients.

Limitations
The findings of this systematic review and meta-analysis should be interpreted within the context of its limitations.Similar to prior reviews, the heterogeneity of studies remains a limitation in the current review. 12,13The heterogeneity of studies can be explained by the heterogeneity of clinical practices 26 across different PICUs (cardiac, surgical, and medical), which may indirectly affect the outcomes of pediatric patients receiving DSI.The majority of patients included had medical diagnoses, and the findings may not be applicable to surgical patients.Larger trials focusing on surgical patients should be considered.Sample sizes of the majority of the included RCTs were also small, which would reduce the power of this study and hence the generalizability of the conclusion.However, the small samples reiterate the dearth of data available for conducting a large RCT before DSI can be recognized as a safe and acceptable sedation strategy for the pediatric population.Most of the RCTs focused on midazolam and morphine; the outcome of DSI using different sedatives and different combinations remains to be fully investigated.While DSI has been shown not to have adverse psychological outcomes in adults, 40 the present study did not examine the long-term psychological or neurocognitive outcomes in pediatric patients receiving DSI.
Moreover, limited data across the 6 RCTs did not allow us to perform meaningful subgroup analyses of the differences in primary outcomes between cohorts with varying medical diagnoses (respiratory vs neurologic) or comorbidities (neurologic vs non-neurologic).Data (eg, assessment for delirium, sedation-free days, and ventilator-free days) that may explain the lack of a detectable difference in sedation burden, with more complete information on adverse events, were also not available.

Conclusions
In this systematic review and meta-analysis, use of DSI was associated with shorter length of PICU stay without increased adverse events but was not associated with a reduction in the duration of MV

Figure 2 .
Figure 2. Duration of Mechanical Ventilation in Daily Sedation Interruption (DSI) vs Continuous Intravenous (IV) Sedation

Figure 3 .
Figure 3. Length of Intensive Care Unit Stay in Daily Sedation Interruption (DSI) vs Continuous Intravenous (IV) Sedation

Figure 4 .-
Figure 4. Risk of Bias Across All Included Studies as Assessed by Independent Reviewers

Table .
Characteristics of the 6 Included Randomized Clinical Trials
and sedative dosing.While this conclusion may be of uncertain clinical significance in view of the limitations of existing systematic reviews on this divisive topic, larger-scale studies delineating the safety profile of DSI in critically ill pediatric patients receiving MV support are needed to strengthen these findings.Additionally, future studies should investigate the association of DSI with improved neurodevelopmental outcomes in PICU survivors.Sedation Dosing in Daily Sedation Interruption (DSI) vs Continuous Intravenous (IV) Sedation eFigure 2. Adverse Events in Daily Sedation Interruption (DSI) vs Continuous Intravenous (IV) Sedation eFigure 3. Subgroup Analysis of Surgical vs Medical Cohort of Patients Receiving Daily Sedation Interruption (DSI) vs Continuous Intravenous (IV) Sedation eFigure 4. Funnel Plot for Length of Stay in PICU eTable 1. Characteristics of Patients Included in Studies eTable 2. Daily Sedation Interruption (DSI) vs Continuous Intravenous (IV) Sedation by Dosing Regimen or by Distribution Across Different Sedative Agents eTable 3. Patient Outcomes in Both Daily Sedation Interruption (DSI) and Continuous Intravenous (IV) Sedation Groups